Table 1 Metabolic signaling regulators that improve CAR-T cell destiny and reverse exhaustion
From: Rewiring mitochondrial metabolism to counteract exhaustion of CAR-T cells
Target | Compounds | FDA approval | Model | Outcome | References |
|---|---|---|---|---|---|
PI3K | LY294002 IC87114 | No | 1. MOLM-13-CD19 cell line 2. NSG mice AML model | Increasing TN and TCM populations of CD33 CAR-T in vivo Improving CAR-T cell persistence and reducing tumor burden in vivo | [119] |
PDK Glycolysis | Dichloroacetate | Yes | 1. Hepatocellular carcinoma (HCC) cell lines 2. HCC-bearing mice model | Increasing TN and TCM percentages Reducing lactate-mediated immunosuppression | [168] |
mTOR | Rapamycin | Yes | Acute lymphocytic choriomeningitis virus infection mice model | Enhancing the formation of memory CD8 T cells during the naïve to effector T cell differentiation phase and the effector to memory transition phase in vivo Improving the functional qualities of the memory CD8 T cells in vivo | [117] |
Akt | A-443654 | No | LCMV-infected mice model | Rescuing short-lived effector cells from deletion due to sustained Akt activation Enhancing P14 CD8 TEM cells in vivo | [118] |
Akt | Akti-1/2 | No | 1. CD19 + lymphoid leukemic cell line 2. CD19 + tumor-bearing immunodeficient mice model | Preventing CAR-T cell differentiation Increasing cytokine production and cytotoxicity Exhibiting greater anti-tumor efficacy and expansion in vivo | [124] |
BATF c-Myc | JQ1 | No | 1. K562 cell line, CD19 + leukemia cell line NALM-6,melanoma cell line A375 2. ALL or melanoma-bearing NSG mice model | Promoting the maintenance of TSCM and TCM phenotypes, persistence and antitumor effects of CAR-T cells in vivo | [169] |
PI3Kγ PI3Kδ | IPI-549 CAL-101 TGR-1202 | No | 1. B16F10 (H-2b) melanoma cell line 2. K562-mesothelinexpressing cell line 3. pmel-1 TCR-transgenic mice model | Sole blockade of PI3Kγ or PI3Kδ, but not dual inhibition, induces a naive/stem memory-like profile and enhances in vivo antitumor immunity of infused CD8+ T cells PI3Kδ inhibition improves cytotoxicity of Meso-CAR T cells | [121] |
PI3Kδ | Idelalisib | Yes | 1. PBMCs fromconsenting DLBCL patients and healthy controls 2. NSG mice model 3. B6 SJL mice lymphoma model | Enhancing the expansion and functionality of CAR-T cells in vitro Enhancing DLBCL patient T cells persistence in vivo Enhancing anti-tumor activity of OT-T cells in a murine lymphoma model | [120] |
PGC-1α PPAR-α | Bezafibrate Fenofibrate | Yes | 1. Melanoma mice model 2. Skin sarcoma BALB/c mice model | Promoting FAO Improving CD8+ TIL functions Synergizing with PD-1 blockade |